THE REGULATORY SUBUNIT OF CAMP-DEPENDENT PROTEIN-KINASE AS A TARGET FOR CHEMOTHERAPY OF CANCER AND OTHER CELLULAR DYSFUNCTIONAL-RELATED DISEASES

Three separate experimental approaches, using site-selective cAMP analogs, antisense strategy and retroviral vector-mediated gene transfer, have provided evidence that two isoforms, the RI- and RII-regulatory subunits of cAMP-dependent protein kinase, have opposite roles in cell growth and differentiation; RI being growth stimulatory while RII is a growth-inhibitory and differentiation-inducing protein. As RI expression is enhanced during chemical or viral carcinogenesis, in human cancer cell lines and in primary human tumors, it is a target for cancer diagnosis and therapy. 8-Cl-cAMP and RI antisense oligodeoxynucleotide, those that effectively down-regulate RI, and up-regulate RII(beta), provide new approaches toward the treatment of cancer. This approach to modulation of RI vs RII cAMP transducers may also be beneficial toward therapy of endocrine or cellular dysfunction-related diseases where abnormal signal transduction of cAMP is critically involved.